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CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor

The chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (CFTR) variants generally correlates with severity of cystic fibrosis (CF). However, 3 adults bearing the common severe variant p.Phe508del (legacy: F508del) and a deletion variant in an ivacaf...

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Autores principales: Raraigh, Karen S., Paul, Kathleen C., Goralski, Jennifer L., Worthington, Erin N., Faino, Anna V., Sciortino, Stanley, Wang, Yiting, Aksit, Melis A., Ling, Hua, Osorio, Derek L., Onchiri, Frankline M., Patel, Shivani U., Merlo, Christian A., Montemayor, Kristina, Gibson, Ronald L., West, Natalie E., Thakerar, Amita, Bridges, Robert J., Sheppard, David N., Sharma, Neeraj, Cutting, Garry R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986068/
https://www.ncbi.nlm.nih.gov/pubmed/35315358
http://dx.doi.org/10.1172/jci.insight.148841
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author Raraigh, Karen S.
Paul, Kathleen C.
Goralski, Jennifer L.
Worthington, Erin N.
Faino, Anna V.
Sciortino, Stanley
Wang, Yiting
Aksit, Melis A.
Ling, Hua
Osorio, Derek L.
Onchiri, Frankline M.
Patel, Shivani U.
Merlo, Christian A.
Montemayor, Kristina
Gibson, Ronald L.
West, Natalie E.
Thakerar, Amita
Bridges, Robert J.
Sheppard, David N.
Sharma, Neeraj
Cutting, Garry R.
author_facet Raraigh, Karen S.
Paul, Kathleen C.
Goralski, Jennifer L.
Worthington, Erin N.
Faino, Anna V.
Sciortino, Stanley
Wang, Yiting
Aksit, Melis A.
Ling, Hua
Osorio, Derek L.
Onchiri, Frankline M.
Patel, Shivani U.
Merlo, Christian A.
Montemayor, Kristina
Gibson, Ronald L.
West, Natalie E.
Thakerar, Amita
Bridges, Robert J.
Sheppard, David N.
Sharma, Neeraj
Cutting, Garry R.
author_sort Raraigh, Karen S.
collection PubMed
description The chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (CFTR) variants generally correlates with severity of cystic fibrosis (CF). However, 3 adults bearing the common severe variant p.Phe508del (legacy: F508del) and a deletion variant in an ivacaftor binding region of CFTR (p.Phe312del; legacy: F312del) manifested only elevated sweat chloride concentration (sw[Cl(–)]; 87–105 mEq/L). A database review of 25 individuals with F312del and a CF-causing variant revealed elevated sw[Cl(–)] (75–123 mEq/L) and variable CF features. F312del occurs at a higher-than-expected frequency in the general population, confirming that individuals with F312del and a CF-causing variant do not consistently develop overt CF features. In primary nasal cells, CFTR bearing F312del and F508del generated substantial chloride transport (66.0% ± 4.5% of WT-CFTR) but did not respond to ivacaftor. Single-channel analysis demonstrated that F312del did not affect current flow through CFTR, minimally altered gating, and ablated the ivacaftor response. When expressed stably in CF bronchial epithelial (CFBE41o(–)) cells, F312del-CFTR demonstrated residual function (50.9% ± 3.3% WT-CFTR) and a subtle decrease in forskolin response compared with WT-CFTR. F312del provides an exception to the established correlation between CFTR chloride transport and CF phenotype and informs our molecular understanding of ivacaftor response.
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spelling pubmed-89860682022-04-07 CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor Raraigh, Karen S. Paul, Kathleen C. Goralski, Jennifer L. Worthington, Erin N. Faino, Anna V. Sciortino, Stanley Wang, Yiting Aksit, Melis A. Ling, Hua Osorio, Derek L. Onchiri, Frankline M. Patel, Shivani U. Merlo, Christian A. Montemayor, Kristina Gibson, Ronald L. West, Natalie E. Thakerar, Amita Bridges, Robert J. Sheppard, David N. Sharma, Neeraj Cutting, Garry R. JCI Insight Research Article The chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (CFTR) variants generally correlates with severity of cystic fibrosis (CF). However, 3 adults bearing the common severe variant p.Phe508del (legacy: F508del) and a deletion variant in an ivacaftor binding region of CFTR (p.Phe312del; legacy: F312del) manifested only elevated sweat chloride concentration (sw[Cl(–)]; 87–105 mEq/L). A database review of 25 individuals with F312del and a CF-causing variant revealed elevated sw[Cl(–)] (75–123 mEq/L) and variable CF features. F312del occurs at a higher-than-expected frequency in the general population, confirming that individuals with F312del and a CF-causing variant do not consistently develop overt CF features. In primary nasal cells, CFTR bearing F312del and F508del generated substantial chloride transport (66.0% ± 4.5% of WT-CFTR) but did not respond to ivacaftor. Single-channel analysis demonstrated that F312del did not affect current flow through CFTR, minimally altered gating, and ablated the ivacaftor response. When expressed stably in CF bronchial epithelial (CFBE41o(–)) cells, F312del-CFTR demonstrated residual function (50.9% ± 3.3% WT-CFTR) and a subtle decrease in forskolin response compared with WT-CFTR. F312del provides an exception to the established correlation between CFTR chloride transport and CF phenotype and informs our molecular understanding of ivacaftor response. American Society for Clinical Investigation 2022-03-22 /pmc/articles/PMC8986068/ /pubmed/35315358 http://dx.doi.org/10.1172/jci.insight.148841 Text en © 2022 Raraigh et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Raraigh, Karen S.
Paul, Kathleen C.
Goralski, Jennifer L.
Worthington, Erin N.
Faino, Anna V.
Sciortino, Stanley
Wang, Yiting
Aksit, Melis A.
Ling, Hua
Osorio, Derek L.
Onchiri, Frankline M.
Patel, Shivani U.
Merlo, Christian A.
Montemayor, Kristina
Gibson, Ronald L.
West, Natalie E.
Thakerar, Amita
Bridges, Robert J.
Sheppard, David N.
Sharma, Neeraj
Cutting, Garry R.
CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor
title CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor
title_full CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor
title_fullStr CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor
title_full_unstemmed CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor
title_short CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor
title_sort cftr bearing variant p.phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986068/
https://www.ncbi.nlm.nih.gov/pubmed/35315358
http://dx.doi.org/10.1172/jci.insight.148841
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